Effect of Huprine X on β-Amyloid, Synaptophysin and α7 Neuronal Nicotinic Acetylcholine Receptors in the Brain of 3xTg-AD and APPswe Transgenic Mice

Abstract

Background: Several studies implicate acetylcholinesterase (AChE) in the pathogenesis of Alzheimer’s disease (AD), raising the question of whether inhibitors of AChE also might act in a disease-modifying manner. Huprine X (HX), a reversible AChE inhibitor hybrid of tacrine and huperzine A, has shown to affect the amyloidogenic process in vitro. In this study, the aim was to investigate whether HX could affect the AD-related neuropathology in vivoin two mouse models. Methods:Tg2576 (K670M/N671L) (APPswe) and 3xTg-AD (K670M/N671L, PS1M146V, tauP301L) mice were treated with HX (0.12 µmol/kg, i.p., 21 days) or saline at 6–7 months. Human β-amyloid (Aβ) was measured by ELISA, synaptophysin by Western blot and α7 neuronal nicotinic acetylcholine receptors (nAChRs) were analyzed by [¹²⁵I]α-bungarotoxin autoradiography. Results: Treatment with HX reduced insoluble Aβ1–40 (about 40%) in the hippocampus of 3xTg-AD mice, while showing no effect in APPswe mice. Additionally, HX markedly increased cortical synaptophysin levels (about 140%) and decreased (about 30%) the levels of α7 nAChRs in the caudate nucleus of 3xTg-AD mice, while increasing (about 10%) hippocampal α7 nAChRs in APPswe mice. Conclusion: The two mouse models react differently to HX treatment, possibly due to their differences in brain neuropathology. The modulation of Aβ and synaptophysin by HX in 3xTg-AD mice might be due to its suggested interaction with the peripheral anionic site on AChE, and/or via cholinergic mechanisms involving activation of cholinergic receptors. Our results provide further evidence that drugs targeting AChE affect some of the fundamental processes that contribute to neurodegeneration, but whether HX might act in a disease-modifying manner in AD patients remains to be proven.

Huprine X and Huperzine A Improve Cognition and Regulate Some Neurochemical Processes Related with Alzheimer’s Disease in Triple Transgenic Mice (3xTg-AD)

“…These results agree with those previously obtained for TACE in middled-aged mice treated with the same dose of huprine X [17]. Moreover, as the long-term treatment with huprine X decreases the levels of insoluble β-amyloid in 3xTg-AD mice [41], we can speculate that it induces non-amyloidogenic APP processing by promoting α-secretase cleavage of APP.…”

Inhibitors of Acetylcholinesterase and Butyrylcholinesterase Meet Immunity

“…Huperzine A can bind to the peripheral anionic site of AChE and the effect is reportedly responsible for amelioration of the amyloidogenic process [92]. Besides AChE inhibition, huperzine A is a potent non-competitive inhibitor of the N -methyl- d -aspartate receptor [78,79].…”

Shogaol–huprine hybrids: Dual antioxidant and anticholinesterase agents with β-amyloid and tau anti-aggregating properties

“…Previous results from in vitro, ex vivo, and in vivo studies have shown that huprine Y and several classes of huprine-based hybrid compounds can readily cross the BBB, leading to central effects. 20,34,43,44 Conversely, phenolic antioxidants usually have low bioavailabilities and inherent difficulties to cross the BBB, 6,9,45 thereby making it imperative the assessment of the ability of the shogaol-huprine hybrids to enter the brain.…”